5, 5-dioxodibenzo [1, 2, 5]-thiadiazepines and intermediates therefor



CH R so'r r 4 SO'I I 7 t 1 H H Formula I Formula II In Formula II, Rrepresents from one to two substituents attached at the 1,2,3, or 4positions of the heterocyclic structure. The positions of this ringsystem are identified by number in Formula II. R substituent is selectedfrom the group consisting of hydrogen, halogen methyl, trifluoromethyl,alkoxy, alkylthio, and alkylsulfonyl, and contains up to four carbonatoms. R is a lower alkyl group having up to four carbon atoms such asmethyl, ethyl, propyl, isopropyl, n-butyl, sec.-butyl, etc., or it is abenzyl group. R is a substituent attached at the 7, 8, 9 or 10 positionof the heterocyclic structure and is selected from the group consistingof hydrogen, halogen, methyl, trifluoromethyl, dimethylamino,dimethylsulfamyl, carbalkoxy, alkylthio, alkylsulfonyl, alkoxy, andalkylanoyl, and, like group R contains up to four carbon atoms. Thesesubstances are useful as chemical intermediates in the preparation of anovel group of psycho tropic agents which are the subject of mycopending application Serial No. 328,460 filed herewith.

The psychotropic agents disclosed and claimed in copending applicationSerial No. 328,460 are compounds having the following formula as well asthe acid addition salts thereof SOH I R2 Alk-N wherein:

R is from one to two substituents selected from the group consisting ofhydrogen, halogen, methyl, trifl-uoromethyl, alkoxy, alkylthio, andalkylsulfonyl and contains up to four carbon atoms;

R is selected from the group consisting of lower alkyl having one tofour carbon atoms, and benzyl;

R is selected from the group consisting of hydrogen, halogen, methyl,trifluoromethyl, dimethylamino, dimethylsulfamyl, carbalkoxy, alkylthio,alkylsulfonyl, alkoxy, and alkanoyl, and contains up to four carbonatoms;

Alk is selected from the group consisting of ethylene and trimethylenehaving up to one alkyl substituent containing up to two carbon atoms;

United States Patent 0 is selected from the group consisting ofpyrrolidino,

piperidino, morpholino, thiamorpholino, 4-R -piperazinc, and aminowherein R and R are selected from the group consisting of alkyl,hydroxyalkyl having up to four carbon atoms, and alkanoxyalkyl having upto seven carbon atoms, and

R contains up to four carbon atoms and is alkyl.

The compounds of the formula immediately above are prepared from thecompounds of the present invention by reaction therewith of anaminoalkyl ester such as a chloride, bromide, iodide, methanesulfonate,p-toluenesulfonate, sulfate, carbonate, etc. of the formula R2 XA1kN R1wherein X is chlorine, bromine, iodine, p-C H SO CH3SOc-, SO4, --OCO2, CH 0CO etc., a corresponding dioxodibenzothiadiazepine of the aboveformula bearing a hydrogen atom in the ll-position according to thefollowing scheme:

The products of the present invention are prepared by the followingreaction sequence:

S0 01 HzN t SUN NOz X I SOiN I a Ra NO2 X l SOiN I a a NH; X

l SOiN (5) R R Formula II NH X Formula III In the structural formulas ofthis reaction scheme, R R and R have the same meaning as above. X refersto a halogen atom selected from chlorine, bromine, and iodine.

The first step involves formation of a2-nitro-2-halobenzenesulfonanilide by reaction of a2-nitrobenzenesulfonyl halide with a 2-bromo, 2-chloro, or2-iodianiline. The 2-nitro-2'-halobenzenesulfonanilide is then treatedwith an alkylating or benzylating agent for introduction of the Rsubstituent onto the sulf'onamide nitrogen atom. The N-substituted2-nitro-2-halobenzenesulfonanilide is reduced in Step 3 to thecorresponding amino compound. The latter is then acylated to form anN-substituted 2- ac'ylamino-2'-halobenzenesulfonanilide in which theacylamino group contains from one to four carbon atoms; that is,formylamino, acetamino, propionamino, butyramino, etc. The acylaminocompounds are designated by Formula III in the above reaction sequencein which R refers to a hydrogen atom or a lower alkyl group having up tothree carbon atoms. These substances are also considered part of thepresent invention as they are uniquely suited to cyclization in Step 5to the products of Formula II.

Step 1 is carried out under conventional conditions for the preparationof sulfonanilides. A suitable procedure involves mixing of the sulfonylhalide and haloaniline in the presence of a strong base such as sodiumhydroxide, sodium carbonate, pyridine, or other strong tertiary organicamine in an inert liquid reaction medium. The latter term is intended torefer to liquid vehicles which do not react with either the sulfonylhalide or substituted aniline to an appreciable extent under theconditions employed for the transformation. For example, water maysatisfactorily serve as the solvent, the reaction being carried out, forinstance, in dilute aqueous sodium hydroxide as in the Schotten-Baumannmethod. Preferred conditions involve the use of an inert organic solventsuch as a hydrocarbon or hydrocarbon ether including benzene, toluene,xylene, or di-n-butyl ether in the presence of at least one molecularproportion of a strong tertiary amine such as pyridine relative to thequantity of sulfonyl halide. The product may be recovered by evaporationof the solvent and neutralization of the residue. Purification byrecrystallization from an appropriate solvent such as ethanol,chloroform, ethyl acetate, methanol, etc., is sometimes desirable. Areaction temperature of about 60-150 C. is preferred in order to hastenthe reaction to completion.

Step 2 involves replacement of the sulfonamido hydro gen atom :by alower alkyl or 'benzyl group. This is conventionally accomplished underordinary conditions of alkylation involving agitating the sulfonanilidefrom Step 1 with at least one molecular proportion of an alkylatingagent such as a mineral acid ester of benzyl alcohol or a lower alkanolincluding dimethyl'sulfate, methyl bromide, diethyl sulfate, benzylbromide, butyl iodide, etc. in the presence of a basic substance ascondensing agent. It is preferred, again, to use an inert liquidreaction medium which includes those mentioned above as well as othernon-hydroxylic or non-acidic solvents such as the hydrocarbon ketonesand esters. Acetone has proven to be a convenient solvent with potassiumcarbonate as the base. In the preparation of the compounds wherein R ismethyl, dimethylsulfate has proven useful as alkylating agent.

Reduction of the nitro group to the amino group is done under conditionswhich are selected to avoid changing other parts of the molecule, forinstance cleavage of the halogen atom. The art has provided a number ofmethods which are satisfactory for carrying out this step. These includereduction of the nitro group with sodium sulfide, ferrous hydroxide,activated iron, or according to a number of other chemical methods.Preferred chemical reductions include the use of stannous chloride andhydrochloric acid employing either ethanol or acetic acid 4 as reactionmedium (Ullmann et al., Ber. 43, 2694 (1910); Ross et al., J. Am. Chem.Soc. 74, 1297 (1952)).

Catalytic methods for reducing the nitro group are also applicable andare in fact more convenient for small scale operation. Hydrogenationover a palladium-on-carbon catalyst at a pressure of from 1 to 3atmospheres employing acetic acid as solvent is quite satisfactory. Fromthe standpoint of convenience, a Raney nickel catalyst with hydrazinehydrate as reducing agent or hydrogen donor is preferred. This method isillustrated in Example 5 hereof.

A-cylation of the 2-an1ino group of the product of Step 3 is carried outin conventional manner. A convenient method is illustrated in Example 6hereof in which the formyl amide is prepared by acylation of theaminosulfonanilide with a mixture of acetic anhydride and foruric acid.Other acylating agents and conditions may be employed as will beapparent to those skilled in the art.

The final step of the synthesis, Step No. 5, involves cyclization toprovide the novel heterocyclic structure which is the subject of thepresent invention. The trans formation is carried out in the presence ofa copper catalyst at elevated temperature. Temperatures of the order of100 to 250 C. are employed. Copper powder or a copper salt such ascuprous carbonate are satisfactory forms. The cyclization may be carriedout directly on the aminosulfonanilide of Step 3 without first acylatingthe amino group as in Step 4, but the method is far less efficient thanthat shown in the reaction scheme and is not practical as a preparativemethod. Vastly superior yields are obtained when using the N-acylatedsulfonanilide of Formula III for the cyclization step. In addition, ithas been observed that the bromo and iodo compounds, Formula III whereinX is bromine or iodine, are superior to the chloro compounds, FormulaIII wherein X is chlorine, since much higher yields are obtained.

The following examples are specific procedures for the preparation of anumber of the novel heterocyclic compounds and intermediates of thepresent invention. These examples illustrate application of thesepreparative methods to the synthesis of various members of the classbearing benzo substituents, that is where R or R are other thanhydrogen.

Example 1.2-nitr0-2-brom0benzenesulfona'nilide Pyridine, 40 ml., iscarefully added to a solution of 44.3 g. (0.2 mole) ofo-nitrobenzenesulfonyl chloride in 500 ml. of benzene and the resultingsolution is treated with 34.4 g. (0.02 mole) of o-bromoaniline. Themixture is then refluxed for 2 hrs., the solvent removed by evaporation,and the residue mixed with about 20 ml. of water to inducecrystallization. The slurry is then acidified and the crude crystallineproduct collected by filtration. It is recrystallized first from ethylacetate and then from a mixture of ethanol and chloroform, yielding 65.5g. (92%) of the desired product as colorless plates, M.P. 147 C.

Analysis.-Br, 22.31; N, 7.92; S, 8.90.

Example 2.-2 nitro N methyl 2 bromobenzenesulfonanilide A mixture of 3.5g. (0.01 mole) of 2-nitro-2'-bromobenzenesulfonanilide, 1.5 g. (0.01mole) of potassium carbonate, and 1.5 g. (0.01 mole) of dimethylsulfatein 50 ml. of acetone is agitated with a mechanical stirrer overnight atroom temperature. After warming the mixture to boiling and filtering toremove insoluble material, the solvent is removed by evaporation. Diluteammonium hydroxide, 20 ml, is added to the residue to destroy excess dimethylsulfate, the residual oil is chilled, whereupon it solidifies. Theyellow solid is recrystallized from methanol affording a nearlyquantitative yield of the desired product. Recrystallization from ethylacetate yields the pure product, MsP. 119 C.

Example 3.-2-nitr0-N-(n-butyl) -2'-br0m0benzenesulfonanilide Example4.-2 nitro N benzyl 2' bromobenzenesulfonanilide The procedure ofExample 2 is repeated substituting benzyl bromide on an equimolar basisfor the dimethylsulfate specified in that example. The desired productis recovered and purified in substantially the same fashion.

Example 5 .2-crmi1z0-N -melhyl-2 -brm0- benzenesulfonanilide A solutionof 6 g. (0.15 mole) of N-methyl-2-nitro-2- bromobenzenesulfonanilide in700 ml. of absolute ethanol is prepared and approximately g. of asuspension of Raney nickel hydrogenation catalyst is added thereto. Themixture is heated to boiling and a solution of 60 ml. of 85% hydrazinehydrate and m1. of absolute ethanol is added in portion-Wise fashion ata rate just suficient to maintain vigorous refluxing due to theexothermic reaction. Approximately 1.5 hrs. is required. The mixture isthen refluxed for an additional 2 hrs., cooled, filtered, and thefiltrate concentrated to dryness. The partially crystalline residue isrecrystallized from ethyl acetate and then from 95% ethanol, yielding intwo crops 44 g. (86%) of the desired product. The Purified product isprepared by recrystallization of this material from ethyl acetate. It isobtained as opaque White prisms, M.P. 139 C.

Alzalysis.Br, 23.43; N, 8.31; S, 9.31.

This substance exhibits absorption maxima in the infrared (1% in KBrpellet) at 2.95 and 3.05 m., as is characteristic or aromatic primaryamines.

Example 6.-2-f0rmyIamin0-N-methyl-2-br0m0- benzenesulfonanilide Amixture of 20.4 ml. of acetic anhydride and 8.6 ml. of 98% formic acidis prepared and g. of N-methyl-Z amino2'-bromobenzenesulfonanilide isthoroughly mixed therewith. The resulting mass is then stirred at C. forone hour, chilled, and mixed with ice Water. The

tan precipitate constituing the desired product is recovered byfiltration and recrystallized from a mixture of isopropanel and heptaneproviding a nearly quantitative yield of the desired product. Thepurified material is obtained by recrystallization from isopropanol, MP.111 C.

Example 7 .2-acetamin0-N methyl-2- bromobenzenesulfonanilide A mixtureof 25 ml. of acetic anhydride and 41 g. (0.12 mole) ofZ-amino-N-methyl-2-'-bromobenzenesulfonanilide is heated to boiling overa free flame for about 5 min. The mixture is allowed to stand at roomtemperature for tWo hours, diluted to 1 l. With Water, and chilledovernight. The mixture is then extracted With four 100 ml. portions ofchloroform, the extracts dried over magnesium sulfate, and the solventdistilled. The residue partially crystallizes. It is twicerecrystallized from isopropanol, yielding the desired product, M.P. -82C.

Arzalysis.-C, 46.88; H, 3.90; S, 8.55.

The procedure or Example 7 may be adapted to the corresponding2-propionamino and 2-butyramino compounds by employing propi onicanhydride or butyric anhydride therein.

Examples 8-27.Benz0-substituled benzenesulfonanilides Thebenzenesulfonyl halides and 2-haloanilines listed in Table I are reactedaccording to the method of Example 1; the resultingZ-nitro-Z-halobenzenesulfonilides are then methylated according toExample 2; the 2-nitro-N- methyl- 2'-halobenzenesulfonilides from thatstep are then reduced according to Example 5; and the 2-amino-N-methyl-Z-halobenzenesulfonanilides obtained are formylated according toExample 6 to yield the series of 2- formylamino N methyl-2'-halobenzenesulfonanilides which are listed in Table I.

TABLE I.2-F O RMYLAMINO-NME THYL-2-HALOBENZENESULFONANILIDES [Examples8-27] Ex. N0. Benzenesulfonyl Halide Product i-Halo-aniline2-nitrobenzenesuliony1 chloride 2-nitro-4-fluorobenzenesulionyl chl0rideZ-nitro-ttoluenesulfonyl chloride 2nitro-4,5-dirnethylbenzcnesulionylchloride.

2-nitro-4-cthoxybenzonesulionyl chloride.

2-nitro-4-rnethoxy-benzenesullonyl chloride2-nitro-4-ch1orobenzenesulionyl chloride. Z-nitrobenzenesullonylchloride 2 nitro-4,6-dimethylbenzenesulionyl chloride-Z-nitrobenzenesulionyl chloride 2-brorno aniline 2chloro'mi1inp2-bromoaniline 2-br0rno-4-dimothylsuliamylaniline. (CHQQ.d-bromoi-aminoaceto- H 4COCH Br phenone.

4,5-(CH3M...

ad0 4,6(CH3)2 2,6dibromoaniline H 2-b1'omo-5-fluoroaniline. 2-bromo5-chloroaniline Z-nit1'0 4-trifiuoromethylbenzenesulfonyl chloride2-nitro-4-brornobenzenosulfonyl chloride 2-nitroben zenesulf0nylchloride 2-bromo-4-methylaniline 2-bromo'5-dimethylaminoaniline Methyl3-arnino-4-brom0- henzoate.

2-br0mo aniline 5C2H5O 3-arnino-4cl1l0r0benzo tritiuoride.2-bromo-5-ethoxyaniline Example 28.6-methyl-5,5-dioxba'ibenzo[1,2,5]thiadiazepine A mixture of g. ofZ-acetamino-N-methyl-2-bromobenzenesulfonanilide, 2 g. of anhydrouspotassium carbonate, and 0.1 g. of copper powder is reflux-ed for 7 hrs.in 70 ml. of dimethylformamide. The mixture is allowed to cool to roomtemperature andthen diluted with ice water. The mixture is chilled inthe refrigerator, resulting in precipitation of the desired product as agray precipitate which is collected, dried in the air, yielding 3.0 g.(88%) of the desired product, M.P. 194-196 C. This material, onrecrystallization from ethanol, yields the purified product, M.P. 201 C.

Analysis-N, 10.71; S, 12.20.

When 2 amino N methyl 2' bromobenzenesulfonanilide is treated withcopper powder and potassium carbonate according to this procedure, thesame product is obtained in low yield and it is extremely difiicult topurify.

Examples 2948.Benz0substituted 6-methyl-5,5- dioxodibenzo [1 ,2,5thiadiazepine Various benzenesulfonanilides of Examples 8-27 (Table I),are treated as described in Example 28, which results in the cyclizationthereof to the corresponding 5,5- dioxodibenzo[1,2,5]thiadiazepines. Theproducts are listed below, along with an identifying example number foreach. The number in parenthesis immediately following the example numberrefers to the benzenesulfon- *anilide intermediate required forpreparation of the identified product.

Example 29 (8 2rnethoxy-6-methyl-5 ,5-dioxodibenzo[1,2,5]thiadiazepineExample 30 (9) --6-methyl-5 ,5 -di0xodibenzo 1 ,2,5

thiadiazepine Example 31 10 2-chloro-5-methy1-5,5-dioxodibenzo- [1,2,5thiadiazepine Example 32 1 1 )-6-methyl-9-dimethylsulfamyl-5, 5-

dioxodibenzo[1,2,5]thiadiazepine Example 3 3 l2 )6-methyl-9-acetyl-5 ,5-dioxodibe nzo- [1,2,5 thiadiazepine Example 34 (13 )2-fluor0-6-methyl-S,S-dioxodibenzo[1,2,5]thiadiazepine Example 3 5 (142,6-dimethyl-S,5-dioxo dibenzo- [1,2,5 thi-adiazepine Example 3 6 (15)2-ethoxy-6-methyl-5 ,5 -dioxodibenzo[1,2,5]thiadiazepine Example 3 7(16 2,3 ,6-trimethyl-5 ,5 -diox0 dibenzo- [1,2,5] thiadiazepine Example3 8 (17 2,4,6-trimethyl-5,S-dioxo dibenzo- [1,2,5 thiadiazepine Example39 (18 6-methyl-7-bromo-5,S-dioxodibenzo[1,2,5]thiadiazepine Example 40(19 --6-methyl-8-fluoro-5 ,S-dioxodibenzo[1,2,5]thiadiazepine Example 41(20 6-methyl-8-chloro-5 ,5 -dioxodibenzo[1,2,5]thiadiazepine Example 42(21 )-6,9-dimethyl-5 ,5 -di0xodibenzo- [1,2,5 thiadiazepine Example 43(22 6-methyl-8-dimethylarnino-5 ,5 -dioxodibenzo[1,2,5]thiadiazepineExample 44 (23 )6-methyl-8-carbomethoxy-5 ,5-dioxodibenzo[1,2,5]thiadiazepine Example 45 (24) 2-bromo-6-methyl-5 ,5-dioxodibenzo[1,2,5]thiadiazepine Example 46 (25)-2-trifluoromethyl-6-methy1-5,5-dioxodibenzo[1,2,5]thiadiazepine 111the preparation of 6-methyl5,5-dioxodibenzo[1,2,5] thiadiazepine from2formylaminO-N methyl-2-chlor0benzenesulfonanilide, the cyclization ismuch less efficient than with the bromo intermediate specified inExample 28. A 20% yield was obtained in this instance as compared to the88% yield of Example 28.

Example 47 (26)6-methyl-7-trifluoromethyl-5,5-dioxodibenzo[1,2,5]tl1iadiazepine Example 48(27)-6-methyl-8-ethoxy-5,5-dioxodibenzo[1,2,5]thiadiazepine Example49.6-(n-butyl)-5,5-di0x0dibenz0- [1,2,5] thiadiazepine 2 formylamino N(n butyl) 2' bromobenzenesulfonanilide is prepared from2-nitro-N-(n-butyl)-2- bromobenzenesulfonanilide by the procedures ofExamples 5 and 6. It is then substituted in the procedure of Example 28for the N-methylbromobenzenesulfonanilide specified therein. The desiredproduct is recovered in substantially the same fashion.

Example 50.6-benzyl-5,5-dloxodibenz0 [1,2,5] llziadiazepine 2formylamino l benzyl 2' bromobenzenesulfonanilide is prepared from2-nitro-N-benzyl-2-bromobenzenesulfonanilide by the procedures ofExamples 5 and 6. It is then treated as described in the procedure ofExample 28. The above named product is recovered in substantially thesame fashion described in Example 28.

Example 51 .7-ethylthi0-6-methyl-5,5-di0x0- dibenzo [1,2,5]thiadiazepine Thirty-four grams (0.1 mole) of 6-methyl-7-bromo-5,5-diox'odibenzo[1,2,5]thiadiazepine, 13 g. (0.1 mole) of cuprous ethylmercaptide (prepared according to Adams and Ferretti, R. Adams and A.Ferretti, I. Am. Chem. Soc. 81, 4927 (1959)), ml. of quinoline and 8 ml.of pyridine is heated at 200 C. for 10 hrs. The mixture is then pouredinto an ice slurry of excess hydrochloric acid. Digestion of theprecipitate with acetone after collecting it by filtration yields a darksolution which is diluted with Et O to precipitate tars. The supernatantis decanted and evaporated and the residue recrystallized from ethanolto give the purified product.

Example 52.7-ethanesulf0nyl-6-methyl-5,5-

dioxodibenzo [1,2,5] thiadiazepine The procedure of Pomerantz andConner, I. Am. Chem. Soc. 61, 3386 (1939) is adapted to thispreparation. One-tenth mole of the product of Example 50 is dissolved ina mixture of 50 m1. of glacial acetic acid and 50 ml. of aceticanhydride and chilled to 0 C. while 27 ml. of 30% aqueous hydrogenperoxide is slowly added. The mixture is kept at room temperature for 3days. Excess peroxide remaining at this time is decomposed by adding apinch of manganese dioxide. The solvent is removed in vacuo and theresidue recrystallized from aqueous ethanol to yield the desiredproduct.

Example 53.2-etltyltlzio-6-methyl-5,5-

dioxodz'benzo [1,2,5] thiadiazepine The method of Example 51 is modifiedto use the prodnet of Example 45 as starting material, resulting information of the desired product.

Example 54.2-ethanesulf0nyl-6-metlzyl-5,5- dioxodz'benzo [1 ,2,5]thiadiazep-ine The method of Example 52 is adapted to use of the productof Example 53 as starting material, yielding the desired product.

While several particular embodiments of this invention are shown above,it will be understood that the invention is not to be limited thereto,since many modifications may be made, and it is contemplated by theappended claims to include any such modification as falls within thetrue spirit and scope of the invention.

X is selected from the group consisting of chlorine,

bromine, and iodine,

and

R is selected from the group consisting of H, and alkyl 2 110 groupconsisting of hydrogen, halogen, methyl, trifluoromethyl, alkoXy,alkylthio, and alkylsulfonyl and contains up to four carbon atoms, R isselected from the group consisting of lower alkyl 5 having one to fourcarbon atoms, and benzyl, and

R is selected from the group consisting of hydrogen,

halogen, methyl, trifiuoromethyl, dimethylamino, dimethylsulfamyl,carbalkoxy, alkylthio, alkylsulfonyl, alkoxy, and alkanoyl, and containsup to four carbon atoms. 2. 2 formylamino 2 bromo N (lower alkyl)-benzenesulfonanilide.

3. 2 acetylamino 2' bromo N (lower alkyl)- benzenesulfonanilide.

4. 2 formylamino 2' bromo N methylbenzenesulfonanilide.

5. 2 acetylamino 2' bromo N methylbenzenesulfonanilide.

6. 6 (lower alkyl) 5,5 dioxodibenzo[1,2,5]thiadiazepine.

7. 6 methyl 5,5 dioxodibenzo[1,2,5]thiadiazepine.

No references cited.

5 WALTER A. MODANCE, Primary Examiner.

JAMES A. PATTEN, Assistant Examiner.

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF